Hepatitis C virus (HCV), originally named “non-A non-B hepatitis” (NANBH), is a positive, single-stranded RNA virus of the Flaviviridae family. Its genome contains a single long open reading frame which encodes a polyprotein of about three-thousand amino acid residues. (Choo et al. (1989) Science 244:359-362). The polyprotein is processed by the host cell and viral proteases into three major structural proteins and several non-structural proteins necessary for viral replication. The nucleotide sequence of HCV is highly variable, the most divergent isolates sharing only 60% nucleotide sequence homology. Several different genotypes of HCV with slightly different genomic sequences have been identified.
Isolates from all over the world have now been grouped into 6 main types, each with several subtypes, based on sequence data (Simmonds et al. (1995) Hepatology 21: 570-83). Types 1-3 account for almost all infections in Europe, type 4 is prevalent in Egypt and Zaire, type 5 in South Africa and type 6 in Hong Kong.
The virus is transmitted primarily by blood and blood products. The majority of infected individuals have either received blood transfusions prior to 1990 (when screening of the blood supply for HCV was implemented) or have used intravenous drugs. Approximately 200 to 400 million people worldwide are chronically infected with HCV, about 2 to 5 million of these are in the United States. The chronic infection of HCV, which effects about 80% of those infected, lasts lifelong and often leads to the development of cirrhosis and liver cancer.
The development of vaccines against HCV has been slowed by the extreme antigenic variability of the virus. Even when available, vaccines will not alleviate the problems faced by millions of chronic HCV carriers worldwide.
Most antibodies to HCV do not play a major role in clearance of infection, although neutralizing antibodies do exist. However, these tend to be strain-specific and are ineffective against emerging strains.
Presently, the only therapy with any demonstrated efficacy against HCV-induced liver disease involves the use of alpha-IFN, but this approach has achieved only limited success. Even the best clinical trials with alpha-IFN treatment report only 40-50% of chronic sufferers respond and 50% of these individuals relapse when treatment is stopped. There is also evidence that alpha-IFN treatment is much less effective against some HCV genotypes than others.
Currently, no conventional drugs against HCV infection (other than alpha-IFN) have yet been developed. Accordingly, improved immunotherapies for treating and preventing HCV infection are needed.